The widespread commercial application of NMR (nuclear magnetic resonance) spectroscopy has been somewhat restricted by the inherent low sensitivity of the technique. This is particularly true for 13C and 15N nuclei, due to their low magnetic moments and natural abundance compared to 1H. The signal to noise ratio (SNR) of NMR may be improved by reducing thermal noise or enhancing signal. The former approach has recently seen increased use through the widespread commercial availability of cryogenically cooled RF probes, despite the fact that it only affords a SNR gain of perhaps a factor five under ideal circumstances. NMR signal increases with magnetic field strength, which is one of the reasons behind the trend for development of ever higher field magnets, but this is an exceptionally costly solution to improved SNR.
An alternative method of boosting signal is dynamic nuclear polarization (DNP). In the absence of an applied magnetic field, nuclei having magnetic moment μ (ie: non-integer spin) will be randomly aligned. When placed in a magnetic field the nuclei will align parallel (spin-up) or anti-parallel (spin-down) with the field (of flux density B). The bulk polarization P of a sample may be determined from the ratios of spin-up and spin-down populations, and is related to the ratio of magnetic and thermal energy:
  P  =      tanh    ⁡          (                        μ          ·          B                          k          ·          T                    )      where T is temperature and k is Boltzmann's constant.
The thermal equilibrium polarization is very weak even in a strong magnetic field. For example, 1H polarization is only 32 ppm at room temperature in a 9.4 T field, and 13C is only 8 ppm. The great attraction of hyperpolarization is the ability to temporarily increase the polarization substantially above the equilibrium level, and make an NMR measurement before the enhanced polarization decays back to equilibrium. Several techniques for achieving hyperpolarization have been reported, but most have technical restrictions which limit their application to specific niche markets (e.g.: hyperpolarized 129Xe gas lung imaging). “Increase in signal-to-noise ratio of >10000 times in liquid-state NMR”, J H Ardenkjaer-Larsen et al, PNAS Vol 100.#18, Feb. 9, 2003 demonstrates a process for hyperpolarizing a wide range of small molecule compounds in liquid solution, from which enhanced NMR spectra may be obtained. The process broadly follows the steps of:    1. Mixing a polarizing agent (a compound containing a free radical, ie: unpaired electron) with the sample. A cryo-protectant such as glycol is usually also added.    2. Cooling the mixture to a low temperature where the electron spin polarization is substantial (>50%), typically using a liquid helium bath pumped to 1-2K.    3. Placing the sample in a strong, homogeneous magnetic field (typically a few Tesla, generated by a superconducting magnet, typically sharing the same cryostat as the sample cooling apparatus). At this temperature and field the electron polarization approaches 100%.    4. Irradiating the frozen sample with microwave radiation at a frequency chosen to excite electron spin resonance (ESR) and cause exchange of energy between the nuclear and electron spin systems, via a complex combination of spin-exchange processes (e.g.: Nuclear Overhauser effect, Solid Effect and Thermal Mixing). Over a period of minutes to hours the irradiation results in a build-up of nuclear polarization to a level significantly enhanced over the equilibrium level (e.g.: several %). In essence polarization is transferred from the electron spin system to the nuclear spin system.    5. Turning off the microwave radiation.    6. Rapidly thawing the sample whilst still in a strong (but now not necessarily homogeneous) magnetic field, typically by dissolution in a hot solvent. If thawing is carried out in about a second or less it has been demonstrated that more than 50% of the hyperpolarization can be retained in the liquid state. This represents three to four orders of magnitude polarization enhancement over room temperature equilibrium.    7. Rapidly transferring the liquid sample to a conventional NMR magnet and acquiring a spectrum in a single shot measurement (e.g.: by a conventional pulse-acquire experiment).
As an alternative to freezing and dissolving, the sample could be melted.
The hyperpolarization PDNP of the target nucleus achieved after irradiation for a time t is approximately:
            P      DNP        ⁡          (      t      )        =      η    ·          tanh      ⁡              (                                            μ              e                        ·            B                                k            ·            T                          )              ·          (              1        -                  ⅇ                                    -              t                        τ                              )      where η is a DNP efficiency factor defining the efficiency of transfer of electron polarization (with moment μe) to the target nucleus (μn), and τ is the hyperpolarization build-up time constant. (η and τ are dependant on many factors, such as T and B).
To achieve a significant signal enhancement it is vital that the sample thawing and NMR measurement steps occur very rapidly. This process must also be very well controlled if good data repeatability is to be achieved. The reasons are as follows. When the microwave irradiation is turned off (at time t0) the hyperpolarization decays back towards its thermal equilibrium level. Because the equilibrium polarization is so small compared to the hyperpolarization, the following expression adequately describes the decay of hyperpolarization after microwave irradiation has ceased:
      P    ⁡          (              t        -                  t          0                    )        =                    P        DNP            ⁡              (                  t          0                )              ·          ⅇ                        -                      (                          t              -                              t                0                                      )                                    T          ⁢                                          ⁢          1                    
The time constant of the decay (T1) is determined primarily by the sample's temperature and the magnetic field to which it is exposed. [T1 also depends on the chemical environment of the nucleus, due to dipole-dipole coupling effects]. In the solid state T1 is related to T and B as:T1∝Bα/Tβwhere α is about 2.5 and β is approximately 2. If the sample is kept frozen and cold in a relatively strong magnetic field the relaxation rate remains relatively long (typically minutes to hours).
After dissolution, T1 in the liquid state is much shorter than in the frozen state, but is less sensitive to temperature and magnetic field. It has been demonstrated that the hyperpolarization will persist for several seconds even at room temperature in the Earth's field.
There are therefore two basic options for DNP-NMR hardware: to move the sample from polarization region to the NMR measurement region as a solid, or as a liquid. In the latter case it is possible to transfer the dissolved sample from a dedicated polarizing magnet to a conventional NMR magnet, as described in the paper by J H Ardenkjaer-Larsen et al, referenced above, as long as the transfer is as fast as possible (a few seconds). However, in the apparatus described in that paper, there is a significant delay and variability caused by the manual transfer of the liquid sample from the polarizing apparatus to the NMR magnet.
If the sample is to be transferred as a solid it is necessary to keep it cold (typically <10K) and in a relatively strong magnetic field (typically >0.1 T). This requires either that these regions are positioned in close proximity, for example within the bore of a single magnet providing both polarization and NMR magnetic field regions, or that an insulated transfer magnet is provided to carry the frozen sample from the separate polarization magnet to the NMR magnet. These solutions are mentioned in the prior art, discussed below.
WO-A-03/023432 and WO-A-02/37132 describe several options for apparatus to carry out the DNP-NMR process with improved performance and repeatability, including making the NMR measurement within the same apparatus as that in which the hyperpolarization was performed. This approach has the advantage of minimising the time taken to transfer the polarized sample from the polarizing region to the measuring region.
The fastest possible “transfer” could be achieved if hyperpolarization and NMR measurement occur in the same position, i.e.: within the same uniform magnetic field region. Whilst this approach has been adopted by one research group for solid-state NMR (“Mechanism of Dynamic Nuclear Polarization in High Magnetic Fields,” C. T. Farrar, D. A. Hall, G. J. Gerfen, S. J. Inati and R. G. Griffin, J. Chem. Physics 114, 4922-4933, 2001), it is generally not especially desirable for two main reasons:    1. The field strength required for NMR is typically 7 T or greater (to achieve sufficient frequency dispersion in the 1H spectrum), whilst that required for DNP is typically less than 3.5 T (because hardware for supplying sufficient microwave power is generally not available or cost effective above 100 GHz, the ESR frequency at 3.5 T).    2. The practical difficulties of packaging the sample cooling, microwave cavity and high-resolution NMR probe to fit within a single uniform field region, and ensuring that they do not interfere with each other whilst maintaining good performance.
It is therefore desirable that the polarizing and NMR field regions have properties individually tailored to their function, but are closely located, preferably within the same apparatus. This fact is recognised in WO-A-0237132, where the suggestion is made that the fringe field of conventional NMR magnet be shimmed to the required homogeneity. However, this is impractical for several reasons:                the amp-tums required to locally shim the fringe field cannot be generated by a conventional superconducting shim        the forces generated between a superconducting shim and the main magnet would be unacceptable        the superconducting shim would destroy the homogeneity of the NMR field region.        
U.S. Pat. No. 6,515,260 also describes apparatus in which there are two separate magnetic field regions within the same magnet bore. The sample is hyperpolarized in one and moved rapidly to the second for NMR measurement. In this apparatus the sample is melted by the application of heat after moving from the polarizing region; no dissolution occurs. However, U.S. Pat. No. 6,515,260 does not describe how to achieve this apparatus in practice, i.e.: how to generate two uniform magnetic field regions in close proximity.
There is therefore a need to construct an improved apparatus able to carry out in-vitro DNP-NMR processes efficiently and in a commercially viable manner.